Stable shaped particles of crystalline organic compounds

ABSTRACT

The present invention provides storage stable, shaped particles of allotropic organic compounds. The particles of the present invention can be shaped according to the desired application. Preferred shapes of such particles are microspheres, particularly those having diameters of about 1 to about 1,000 microns. The stable shaped particles of the present invention are particularly well-suited to the fabrication of pharmaceutical formulations, particularly where sustained release and uniform bioavailability are desired. The storage stable particles are formed by a solid state crystallization of allotropic organic compounds. The solid state crystallization process of the present invention affords a means for achieving a storage stable crystalline form of said allotropic compound without loss or deterioration of the original particle dimensions.

This application is a division of U.S. Ser. No. 09/030,388, filed Feb.25, 1998 now U.S. Pat. No. 6,287,693.

BACKGROUND OF THE INVENTION

It is well known that many substances are prone to crystallize indifferent manners, depending on the conditions under which they arecrystallized. Different crystalline structures resulting fromcrystallization of a particular substance are called polymorphs orpseudopolymorphs. It is also known that, when they are melted and cooledrapidly below their melting point, i.e. melt-congealed, the atoms ormolecules forming most substances need some time to arrange themselvesin the order most natural for the environment in which they are placed.Accordingly, they remain in unstable amorphous or semiamorphous statesor organize into metastable polymorphs.

Metastable polymorphs may be enantiotropic, which is a property ofcertain substances meaning that they can exist in more than one crystalform (Giron, Thermal Analysis and Calorimetric Method in theCharacterization of Polymorphs and Solvates, Thermochimica Acta, 248(1995) 1-59; Parker, Dictionary of Scientific and Technical Terms,McGraw Hill, Inc., 1984, 541; Hancock et al., Characteristics andSignificance of the Amorphous State in Pharmaceutical Systems, J. Pharm.Sci., Vol 86, No. 1, 1997, 1-12). Often, there is a relation between thevarious crystal forms or habit of an enantiotropic substance such thatone form is stable above the transition-point temperature and the otheris stable below it. Consequently, the crystal habit is dynamic andreversible depending on ambient conditions.

Metastable polymorphs often transform over time into more stablestructures. This natural crystallization process is called “aging”, andoccurs over time without human intervention. This natural “aging”process is often lengthy and unpredictable, and therefore is costly andpotentially dangerous, particularly in the manufacture ofpharmaceuticals. The unpredictability arises since the aging processlargely depends on environmental factors. Yu, “Inferring ThermodynamicStability Relationship of Polymorphs from Melting Data”, J. Pharm. Sci.,Vol 84, No. 8, 966-974 (1995).

Nevertheless, stable, crystallized substances are generally required foroptimum and reliable bioactivity and bioavailability. If metastableparticles, for example, microspheres or pellets, are placed in anaqueous medium before full crystallization occurs, deformation ofparticle shape or even complete destruction of the particles can occurin a matter of hours.

Furthermore, different polymorphs of a particular substance will havedifferent dissolution rates, resulting in a lack of stability and lossof uniformity between different batches of the same drug. For example,Haleblian et al report differences in dissolution rates betweenpolymorphs of fluprednisolone. Haleblian et al. “Isolation andCharacterization of Some Solid Phases of Fluorprednisolone”, J. Pharm.Sci., Vol. 60, No. 10, 1485-1488 (1971).

For pharmaceutical applications, it is particularly important to achievestable crystallization, because administration of a therapeutic compoundoften requires suspension in an aqueous solution suitable for injection.Also, even if the compound is not first suspended in an aqueous medium,when it is administered to the patient it is subjected to biologicalfluids that are water based. The same is true for pellets and implantsthat are placed in the body through a surgical or other procedure. Toassure the physical integrity of the shaped particles and uniformrelease of the, active agent, it is necessary to assure fullcrystallization prior to administration.

Some workers have attempted to improve the stability of therapeuticcompounds by inducing crystallization. For instance, Matsuda et al.suggest modifying crystalline structures using a temperature controlleddispersion drying method. Matsuda et al. “PhysicochemicalCharacterization of Sprayed-Dried Phenylbutazone Polymorphs”, J. Pharm.Sci., Vol 73, No. 2, 73-179 (1984).

However, because dissolution of a solid is also related to surfaceerosion, the shape and size of the therapeutic particles must also beconsidered in addition to solubility. Carstensen, “PharmaceuticalPrinciples of Solids and Solid Dosage Forms”, Wiley Interscience, 63-65,(1977). Thus, when a pharmaceutical compound is administered as a solidor suspension, the preservation of particular shape and size becomes animportant factor for assuring the control and reproducibility ofbioavailability and biodynamics.

With this in mind, Kawashima et al. proposed a method of sphericalcrystallization of Tranilast through the use of two mutually insolublesolvents, and conversion of the resulting polymorphs by means of heat.Rawashima et al., “Characterization of Polymorphs of Tranilast Anhydrateand Tranilast Monohydrate When Crystallized by Two Solvent ChangeSpherical Crystallization Techniques” in J. Pharm. Sci., Vol 80, No. 5,472-477 (1981).

It has also been reported that the natural process of aging can beaccelerated through heating. Ibrahim et al., “Polymorphism ofPhenylbutazone: Properties and Compressional Behavior of Crystals” in J.Pharm. Sci., Vol 66, No. 5, 669-673 (1977); Hancock et al.,Characteristics and Significance of the Amorphous State inPharmaceutical Systems, J. Pharm. Sci., Vol 86, No. 1, 1-12 (1997). Insome cases, however, the heat required is such that the integrity orshape of the substance is compromised. In several cases where heat hasbeen used, reproducibility of results, stability, and hence control ofcrystal size within particles has been difficult or even impossible toachieve.

In addition, in some cases the most stable polymorph of a particularsubstance is a hydrate, rendering it impossible to reach the desiredpolymorph by means of heat due to resulting dehydration. Furthermore,heating is rarely appropriate for stable crystallization in the case ofmixtures. Thus, the process of heat as a method for obtaining stablepolymorphs, though superior to the aging process, has significantlimitations.

Other workers have studied the use of solvent vapors to inducecrystallization of polymeric species. Such efforts include putativecrystallization and change of the mechanical properties of polymericcompounds, as described in U.S. Pat. No. 4,897,307. See also Müller, A.J. et al., “Melting behavior, mechanical properties and fracture ofcrystallized polycarbonates” in Latinoamericana de Metalurgia yMateriales, 5(2), 130-141 (1985); and Tang, F. et al., “Effect ofSolvent Vapor on Optical Properties of Pr/sub 4VOPe inpolymethylmethacrylates”, in Journal of Applied Physics, 78(10), 5884-7(1995).

Tang et al. used organic solvent vapors to transform a polymer matrix,Pr4VOPc dye (Vanadyl Phtalocyanine having 4 propyl substituents) fromglassy phase I to crystallized phase II. Muller and Paredes describe thecrystallization of polycarbonate polymers in terms of the incorporationof solvents or plasticizers into the amorphous state. To the knowledgeof the present inventors, such an approach has not been used to formstable crystals of melt-congealed organic compounds and mixtures.

SUMMARY OF THE INVENTION

The present invention provides reproducible, stable particles ofcrystalline organic compounds. The stable particles of crystallineorganic compounds of the present invention might be homogeneousparticles of a singular organic compound, or they might be mixtures oftwo or more organic compounds. The stable particles of the presentinvention retain a constant shape and size during prolonged storage,such as in an aqueous suspension. Such stable particles can befabricated to a uniform size and shape, and will retain said size andshape despite long term storage; and thus, are particularly advantageousin pharmaceutical formulations. The present invention further provides amethod for obtaining such reproducible, stable particles. The methodinvolves exposing the above shaped particles, wherein the one or moreorganic compounds is in a crystalline, amorphous, or some metastableform, to an atmosphere saturated with solvent vapors. The solvents arecomprised of one or more liquids in which at least one or more of theorganic compounds is soluble.

The method of the present invention affords several advantages. It isapplicable to substances where the most stable polymorph is a hydrate,because it does not drive off water molecules and thereby allows theincorporation of water molecules into the crystalline web duringformation. It is applicable to thermolabile substances, since hightemperatures are avoided. And it allows stable structure formationinvolving a mixture of substances, which, with the exception of theeutectic mixture-composition, can not be attained by means of heat.

More particularly, the present invention involves a method ofcrystallizing or recrystallizing an amorphous or metastable crystallineorganic compound or mixture. The method comprises the steps of (i)exposing said compound or mixture to an atmosphere saturated with thevapors of one or more liquids, at least one of which must be a solventfor said compound or mixture, for a time sufficient for transforming themetastable compound or mixture to a stable, crystallized compound ormixture; and (ii) recovering the stable, crystallized compound ormixture for storage or use.

The method may be performed using any enclosure where the volume,temperature, and atmospheric content and pressure can be manipulated.The chamber is capable of containing an atmosphere saturated with thedesired solvent vapors. The point of saturation is reached when thevapors fill the chamber without causing condensation on the surfaces ofthe chamber or the particles.

Preferably the particles are formed into a shaped particle, such as amicrosphere, pellet or implant form. Particles configured to haveuniform and reproducible surface area are especially preferred. This canbe effected by melt-congealing. Further, the shaped particles arepreferably configured into a uniform particle size or range of sizes. Tothis end, the methods described in U.S. Pat. Nos. 5,633,014, 5,643,604,and 5,360,616 can be used, which are herein incorporated by reference.Alternatively, any suitable method that results in a metastablecrystalline conglomeration can be used. Where the method involvescrystallization of a mixture, the mixture may be eutectic ornoneutectic.

The particles are placed in the chamber or other suitable enclosureusing any suitable means such that they are exposed to solvent vapors,but not immersed in or otherwise contacting liquid solvent. Theparticles are stationary or mobilized within the chamber.

The time period necessary for effecting crystallization in accordancewith the present method will vary depending on various physicochemicalproperties consistent with established principles. For example, theoptimal time of exposure will vary depending on the shape and size ofthe particle, the chemical makeup of the particle, the form of the solidstate of the particle (i.e., amorphous, metastable crystalline), thetype and concentration of solvent used, and the temperature of thetreatment. Generally, a range of several seconds to 48 hours is applied,or more preferably, 1 to 36 hours. Previous partial crystallization ofparticles does not appear to modify these time ranges. Optimization ofthe time of exposure will vary depending on the solvent system used, theorganic compound(s) to be crystallized, and other variables, and iswithin the skill of one of ordinary skill in the art. As shown below, a24 hour exposure time will commonly be effective.

One advantage of the present invention is that it is applicable tothermolabile substances because high temperatures may be avoided. Thus,the applicable temperature range is broadly defined and dependent on theparticular compound. Generally, the temperature of the vapor atmosphereis sufficient to obtain vaporization of the solvent, but below themelting point of the particles.

The solvent or solvents used in the method of the present invention canbe any agent classified as a solvent for the organic compound(s) ofinterest. As will be appreciated by any ordinarily skilled worker in theart, the selection of solvent will depend on the compound(s) sought tobe stabilized. Exemplary solvents are conventional laboratory liquidsolvents such as water, alkanes, alkenes, alcohols, ketones, aldehydes,ethers, esters, various acids including mineral acids, carboxylic acidsand the like, bases, and mixtures thereof. Some specific exemplarysolvents are methanol, ethanol, propanol, acetone, acetic acid,hydrochloric acid, tetrahydrofuran, ether and mixed ethers, pentane,hexane, heptane, octane, toluene, xylene, and benzene. Water is anespecially useful component of a solvent/liquid mixture of the presentinvention, particularly where the most stable polymorph of a substanceis a hydrate. Generally, solvents suitable for conventional liquidrecrystallization of the compound of interest are suitable as a solventin the present method.

The compound(s) of the stable particles of the present invention includeany organic compound capable of existing as a crystalline solid atstandard temperature and pressure. A preferred embodiment of the presentinvention is that wherein the particles are comprised of one or moreorganic compound(s) capable of forming into a stable crystalline solid.Preferably, the stable crystalline solid is a lattice of discreteorganic molecules, i.e., non-polymeric.

Also preferred are organic compounds having some pharmacological ortherapeutic activity. Still more preferred are such pharmacologicalcompounds susceptible to the formation of polymorphs. Preferredembodiments further include particles comprised of a steroid or sterol,such as estrogen, 17β-estradiol, testerone, progesterone, cholesterol,or mixtures thereof. These mixtures can also includeOxatomide/Cholesterol, Niphedipine/Cholesterol, Astemizol/Cholesterol,which have non-steroidal components. Stable shaped particles of otherorganic compounds are also provided by the present invention, e.g.,Cisapride, Oxatomide.

Because the method of the present invention results in significantstabilization of particles of amorphous or metastable crystallineorganic compounds, the particles of the present invention can be storedin liquid suspension, such as aqueous medium, or administered directlyto a patient. Because the present invention provides stable forms ofexisting pharmacological agents, it will be understood by those skilledin the art that the particles of the present invention can be used inaccordance with conventional practice in analogous formulations, e.g.,the parenteral administration of microspheres, administration ofpharmacological agents via implants, etc.

DETAILED DESCRIPTION OF THE INVENTION

All publications and patent applications referenced herein areincorporated by reference to the same extent as if each individualpublication or patent application was specifically and individuallyindicated to be incorporated by reference.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the preferred methodsand materials are described.

The present invention provides stable shaped particles of one or moreallotropic molecular organic compounds. Allotropic organic compounds arethose capable of assuming two or more distinct physical forms (e.g.,assuming different crystalline forms or an amorphous versus acrystalline form). Such allotropic species are also referred to aspolymorphs or polymorphic species.

The storage stable, shaped particles of the present invention optionallyfurther comprise pharmaceutically acceptable excipients, stabilizers,and buffers as are commonly known among those in the pharmaceuticalarts.

These stable shaped particles possess an advantageous combination ofphysicochemical properties. First, the particles are configured intodesired shapes by means that might not result in the most stablecrystalline form of the constituent organic compound. The particles arethen subjected to a solid state crystallization process that results inthe organic compound assuming the most stable crystalline structure, andfacilitates the retention of the size and shape of the originalparticle. The resultant product is a particularly configured particlecomprised of one or more molecular organic compounds, each having auniform crystalline character and possessed of a high degree of storagestability.

The combination of the uniformity of size and shape of the particle andthe uniformity and stability of the crystalline structure of theconstituent organic compound lends particular predictability andconsistent bioavailability and associated biodynamics.

More particularly, the particles are pre-fabricated to desiredspecifications, e.g., microspheres of particular size and shape. Theparticles are then subjected to a solid state crystallization processthat stabilizes the compounds of the particles without loss of thepre-fabricated size and shape. The resulting particles have greateruniformity of size and shape, more uniform and predictable dissolutionprofiles, and greater storage stability in various forms, e.g., inliquid suspension such as aqueous media or other storage liquid, aslyophilized solid, or alone as a powder or dry solid. By storage stableis meant the particles have improved shelf life without loss of thedesired uniform size and shape of the particles, per se. That is, if thedesired particle shape is a microsphere, the particles will retain aspherical shape of constant size over periods exceeding several years.

As used herein, storage stable refers to retention of the original sizeand shape of the particle, as well as the pharmacological activity ofthe active agent over a period of at least one month.

The present invention also involves a method of crystallizing shapedparticles of a metastable compound or mixture of compounds withoutdissolution of the particle and attendant loss of the desired shape. Thecrystallization process is effected by exposing said particles to acontrolled atmosphere saturated with the vapors of a solvent orsolvents. The atmosphere is optionally modified in other respects, e.g.,pressure, temperature, inert gases, etc. Preferably, the controlledatmosphere is saturated with a solvent vapor but not so much as toeffect condensation of said solvent.

More particularly, the method of the present invention involveseffecting crystallization of an amorphous or metastable organic compoundin a shaped particle without alteration of the dimensions (e.g., sizeand shape) of said particle comprising: (i) exposing said shapedparticle to an atmosphere saturated with the vapor of a liquid, saidliquid being a solvent for said organic compound; and (ii) recoveringsaid shaped particle wherein said organic compound is of a uniformcrystalline structure.

Alternatively stated, the method involves effecting a solid statecrystallization of a molecular organic compound in a particle ofdefinite size and shape comprising: (i) exposing said particle to anatmosphere saturated with a solvent for said organic compound; and (ii)recovering said particle, wherein said organic compound in saidrecovered particle is of a uniform crystalline structure, and saidrecovered particle has retained said size and shape. Retaining the sizeand shape of the particle is meant to include minor variations in thedimensions of the particle, e.g., no more than about 15%; andpreferably, no more than about 10%.

The present invention provides a means for fabricating particles ofdesired dimension without regard to the resulting allotropic form of theorganic compound. After the particle is fabricated into the desiredshape and size, the solid state crystallization can be effected tocrystallize the organic compound into a storage stable solid state ofuniform crystal structure. Moreover, the solid state crystallization ofthe present invention can be effected on particles comprised of morethan one allotropic organic compound.

Preferably, the shaped particle is a microsphere; and, as a result ofthe present process, the organic compound(s) of the microsphere areordered into a single, homogeneous crystalline form without anydeterioration in the size or shape of the microsphere.

For purposes of the present invention, the term “crystallization” refersto a process by which the most stable polymorph of a particularsubstance is achieved. Recrystallization refers to a process similar tocrystallization except that the organic compound of the particle, ratherthan being amorphous, was initially only partially crystalline, of amixed crystalline habit, or crystalline, but of a less stablecrystalline form. Unless indicated otherwise, the term crystallizationincludes recrystallization.

The term “solid state crystallization” refers to a crystallizationprocess that is effected without macroscopic dissolution of the compoundbeing crystallized. As used herein, solid state crystallization includesa crystallization process wherein an organic compound within a shapedparticle is crystallized or rescrystallized by expo.sure to a solventvapor without loss or alteration of the shape or size of the particle.It will be appreciated by those skilled in the art that while subtleintermolecular changes will be effected by such crystallization (e.g.,creation or rearrangement of crystal lattice structure), the microscopicand/or macroscopic dimensions of the particle will not be appreciablyaltered.

The term “saturated” when used in reference to the atmosphere whereinthe crystallization is conducted means that the atmosphere within thechamber or enclosure used to hold the solvent vapors contains themaximum quantity of said solvent in the vapor phase without effectingvisible condensation on surfaces within the chamber. Condensation doesnot include microscopic condensation on the surface of the particlesthat does not affect their shape.

The term “solvent” refers to a liquid at standard temperature andpressure, and one capable of solubilizing an appreciable amount of aspecified solid solute. The solid solute will be a particular organiccompound. Solids vary from 0-100% in their degree of solubility. See,e.g., “Solubility Parameters of Organic Compounds”, CRC Handbook ofChemistry and Physics, 62d ed., C-699, CRC Press; N. Irving Sax andRichard J. Lewis, Sr., Hawley's Condensed Chemical Dictionary, 11^(th)ed., 1079 (1987). For purposes of the present invention, a liquid willbe a considered a solvent with respect to a particular solid soluteprovided the solute is at least 10% soluble in said liquid.

The term “particle” refers to a discrete collection of a plurality ofmolecules of one or more organic compounds. As used herein, a particlemay be an ordered collection (e.g., crystalline) or disorderedcollection (e.g., amorphous) of molecules, or any combination thereof.The term embraces, among other things, microscopic as well asmacroscopic particles such as powders, microspheres, pellets, implants,and the like.

Preferably, particles are made of microspheres. The preferredmicrospheres of the present invention range in size from 1 micron to 1millimeter, more preferably 1 to 500 microns, and most preferably in therange of 1 to 100 microns, particularly for human use. When theparticles are in pellet form, such particles are normally but notnecessarily cylindrical with lengths of 1000 to 5000 microns anddiameter or 500 to 1000 microns. These particles can have importantapplications for veterinary use, and are not injected but depositedunder the skin.

The size and shape of the particle will depend on the intendedapplication and the constituent organic compounds). For example,microsphere size is chosen for practical reasons, i.e a size appropriatefor administration using a hypodermic needle or for assuring a desiredrate of dissolution.

The term “molecular organic compound” refers to an organic compoundexisting as stable discrete molecules (i.e., non-polymeric) and whencombined with a plurality of identical molecules is capable of assumingone or more ordered crystalline structures. Thus, a molecular organiccompound is meant to distinguish from a polymeric species.

The term “metastable” means a pseudoequilibrium state of a solidsubstance where the content of free energy is higher than that containedin the equilibrium state. For our particular purposes, a “stable”substance or particle has a crystalline structure whose shape remainsunchanged in a standard ambient environment, e.g. in air having varyinglevels of moisture, for an extended period of time. However, it shouldbe understood that “stable” does not indicate infinite stability, butmeans sufficiently stable such that the particles remain sufficientlystable for the preservation of their crystalline characteristics duringstorage and up to their application and use and additionally, after theyhave been administered to a subject, up to their total dissolution.

The present invention also encompasses stable microspheres achievedusing the present method. Such microspheres preferably contain acompound having pharmaceutical applications. The microspheres andpellets of the present invention are useful in human, as well as animal,therapeutic regimens.

For instance, there is currently a need for compositions that accomplishthe sustained release of steroid growth promoters in food animals topromote the growth of such animals. The amount of growth hormoneadministered to an animal would depend on the particular animal species,hormone, length of treatment, age of animal, and amount of growthpromotion desired. Other considerations to be made in the use ofhormonal compositions in the treatment of animals are discussed in U.S.Pat. No. 5,643,595, which is herein incorporated by reference. Theparticles of the present invention can be particularly configured foroptimal delivery by injection by varying the particle size.

As discussed above, the microspheres of the present invention are stablein aqueous fluids, and are thus amenable to parenteral injection. Modesof administration include but are not limited to intra-venous (IV),intra-arterial (IA), intra-muscular (IM), intra-dermal, sub-cutaneous,intra-articular, cerebro-spinal, epi-dural, intra-peritoneal, etc. Inaddition, the compounds of the present invention can be administered viaan oral route, either as an aqueous suspension or a lyophilized product.Other routes of administration are also acceptable, including topicalapplication, into the eye, or via inhalation in the form of droplets ormist.

The dosage form according to the present invention may take the form ofa microsphere powder in vials/ampoules, ready to be prepared assuspensions, or take the form of ready-prepared suspensions, packagedinto injectable ampoules or directly into syringes, ready to beadministered in human or veterinary medicine. The suspension medium maybe water, a saline solution, an oil, containing buffers, surfactants,preservatives, commonly used by pharmacotechnicians for preparinginjectable substances or any other substance or combination which doesnot threaten the,physical and chemical integrity of the substances insuspension and which is suitable for the organism which will receive it.If it is desired to avoid a sudden initial increase in the level ofactive ingredient in the internal medium of the receiving organism, itwill be preferable in the case of ready-for-use suspensions to useliquid vectors in which said active ingredients are practicallyinsoluble. In the case of active substances partially soluble in thelukewarm liquid vector but insoluble at cold temperature, it ispreferable, from the pharmacological point of view, to avoid theformation of precipitates (called “caking” effect) by preparingformulations in the form of separate microsphere powder and liquidvector which will be mixed only at the time of injection.

In veterinary applications, where the duration of the desired effect maybe very long (for example the lactation period of the adult female),diameters of a few hundreds of microns may be used. If it is desired tolimit the diameter of injection syringe needles for the comfort of thepatient, the diameter of the microspheres should be limited to 300microns and more preferably to 100 microns. In contrast, for very shortdurations of effect (for example circadians), the diameter of amicrosphere may be reduced to 5 microns.

For most applications in human medicine (duration of action of theactive ingredient between a circadian cycle and a menstrual cycle), itis preferable to use microspheres whose diameter is between 5 and 100microns, depending on the combinations of active substances/carriersubstances.

A separation of microspheres according to their diameter may beperformed during the manufacturing process using known processes: forexample, by cyclonic separators, by sieving using air suction or bysieving in aqueous medium. In practice, it is sufficient if more than70% of the microspheres have diameters of between 70% and 130% of aspecified diameter. If necessary, the ideal dissolution curve,determined by the proposed application, may be approached by mixingbatches with suitable different diameters. Moreover, particles which donot comply with the specifications may be recycled.

The mechanism by which substances in a solid state crystallize in thepresence of vapors containing at least one solvent has not yet beenestablished. The crystallization process may well conform, as regardsthe effect of the solvents, to the traditional principles that apply insaturated solutions and in molecular mobility. It is possible that somemolecular rotational or transference movement occurs, which seems todepend on the particular type of solvent used and to the temperature ofvaporization. Hancock et al., “Characteristics and Significance of theAmorphous State in Pharmaceutical Systems”, J. Pharm. Sci., Vol 86, No.1, 1-12 (1997). It is clear however that the temperatures at which thecrystallization is obtained are well below vitreous transitiontemperatures and are in fact only in accordance with that required forthe solvents' vapor pressure.

Without wishing to be bound by any theory, we contemplate that the vapormolecules of the solvent or solvents might form microcondensations andminute accumulations of solvent on the surface of the particles to becrystallized, thus bringing sufficient energy for the surface moleculesof the solid particles to form organized structures (e.g., crystallinedomains).

By the same token, if present in the vapor, water molecules becomeavailable for the formation of hydrates, when required for stablepolymorphs.

Once the organizational and/or water absorbing process starts at thesurface, it is possible that the crystallization process graduallyspreads into the interior of the particle without the need for contactwith or dissolution within the solvent.

If this is correct there are two facts which seem to indicate that thesemicrocondensations or molecular agglomerations are extremely minute.First, if enough solvent condensation occurred on the surface of theparticle, the solvent would at least partially dissolve it and modifyits shape. To avoid any partial dissolution, the amounts deposited bythe vapor must be extremely minute.

Second, during exposure to solvent vapors the particles, because oftheir small size and large quantity, inevitably come to contact with oneanother. Were there to be any surface dissolution of the particles, aswould occur if the substantial quantities of amounts of deposited vaporwere not very minute, the particles would tend to stick to each otherand form lumps or agglomerates. Under the conditions described herein,this does not occur.

EXAMPLES

The following examples illustrate how a substance or mixtures ofsubstances are transformed from metastable to more stable crystallinestructures according to the method of the present invention.

Example 1 Microspheres of 17β Estradiol

This and other substances were melt/sprayed into droplets and latercongealed into microspheres to be suspended in a water medium forextended release injectables.

Microspheres of 17β estradiol obtained after congealing their sprayeddroplets at −50° C. showed a high proportion of amorphous matter.

Heating these microspheres sufficiently allowed the amorphous matter tocrystallize into an anhydrous polymorph. However, despite being fullycrystallized, these microspheres remained stable at room temperature butunstable when placed in water, due to the fact that the stable polymorphis a hemihydrate (Salole, The Physicochemical Properties of Estradiol,J.-Pharm-Biomed-Anal., 1987:5(7), 635-648; Jeslev et al., Organic PhaseAnalysis, II. Two unexpected cases of pseudopolymorphism, Arch. Pharm.Chemi. Sci. Ed., 1981, 9, 123-130). Thus, in aqueous solution, thesubstance spontaneously reverted to this more stable polymorph and in sodoing restructured its crystalline arrangement into shapes whichdiffered from the microsphere.

When these microspheres were placed in a recipient of approximately 7liters and exposed for 24 hours at 20-25° C. to the vapors of 13.5 mL ofa (50-50) mixture of ethanol and water kept in a porous cellulosematerial, the initially amorphous microspheres crystallized directly inthe presence of the vapors into the stable hemihydrate polymorph andwere thereafter stable when placed in water.

To evaluate the stability of the crystallized 17β Estradiolmicrospheres, the microspheres were placed in aqueous solution at 40° C.and observed by optical microscropy after 274 days. Thus, the stabilityin water of the microspheres containing the hemihydrate form may beverified using optical microscopy.

The residual ethanol present in the microspheres was less than 0.01%.

Example 2 Testosterone Microspheres

Several authors have reported that testosterone has several polymorphs,of which two hydrate forms are stable in water (Frokjaer et al.,Application of Differential Scanning Calorimetry to the Determination ofthe Solubility of a Metastable Drug, Arch. Pharm. Chemi. Sci. Ed., 2,1974, 50-59; Frokjaer et al., Dissolution Behavior InvolvingSimultaneous Phase Changes of Metastable Drugs, Arch. Pharm. Chemi. Sci.Ed., 2, 1974, 79-54; Thakkar et al., Micellar Solubilization ofTestosterone III. Dissolution Behavior of Testosterone in AqueousSolutions of Selected Surfactants, J. Pharm. Sci., Vol 58, No. 1,68-71).

Testosterone microspheres, immediately after being produced by the samespray/congealing as for 17β estradiol, showed an equally high amorphouscontent. Heating the microspheres at 117° C. for 23 hours crystallizedthem into an anhydrous polymorph similar to that found in the commercialraw material. However, when these microspheres were placed in water, theanhydrous polymorph spontaneously converted into a hydrated structure, aconversion that caused the microspheres to lose their shape.

In contrast, when these microspheres were placed in a recipient ofapproximately 7 liters and exposed for 24 hours at 20-25° C. to thevapors of 40 mL of a (80-20) mixture of acetone and water kept in aporous cellulose material, initially amorphous microspheres crystallizeddirectly in the presence of the vapors into the stable hydratepolymorphs mentioned earlier. These crystalline particles exhibitedstorage stability when placed in water.

To evaluate the stability of the testosterone microspheres, themicrospheres were placed in aqueous solution at 40° C. and visualizedafter 54 days by optical microscopy. For comparison, non-crystallizedtestosterone microspheres (melt-congealed only) were also placed inaqueous solution and visualized after 40 days. The stability in water ofthe microspheres containing the hydrate polymorphs versus thenon-crystallized microspheres was apparent by comparing the opticalmicroscopy photographs.

The residual ethanol present in the microspheres was less than 0.01%.

Example 3 Progesterone Microspheres

Progesterone microspheres, immediately after being produced by the samespray/congealing as for the previous substances, showed somecrystallization in polymorphs I and II. No hydrate polymorphs have beenreported for progesterone.

However, when the microspheres were placed in a recipient ofapproximately 7 liters and exposed for 4 hours at 20-25° C. to thevapors of 13.5 mL of a (50-50) mixture of ethanol and water kept in aporous cellulose material, the initially amorphous microspherescrystallized directly in the presence of the vapors into the stablepolymorph I and were thereafter stable when placed in water.

To evaluate the stability of the crystallized Progesterone microspheres,the microspheres were placed in aqueous solution at 40° C. and observedby optical microscropy after 187 days.

It should also be noted that in the case of progesterone, the use ofsolvent vapors also provoked the conversion of polymorph II, present inthe mixture of structures found after spray-congealing, into polymorphI, as observed by DSC.

In addition, in the case of progesterone, the exposition to solventvapors was also successfully obtained with a mobile system. Themicrospheres were placed in a 1.6 liter hermetic crystallizing chamberturning at 5 RPM and placed in contact with ethanol vapors for 24 hours.

In both experiments the residual ethanol present in the microspheres wasless than 0.01%.

Example 4 Astemizole Microspheres

To demonstrate that the method of the present invention was successfulin forming stable crystals of organic compounds other than steroids andsterols, astemizole microspheres were subjected to the solvent vaportreatment.

Immediately after being produced by the same spray/congealing as for theprevious substances, astemizole microspheres also showed a highamorphous content. However, when 100 mg microspheres were placed inrecipient of approximately 0.5 liters and exposed for 24 hours at 30°C., to the vapors of 0.5 mL of ethyl acetate kept in a porous cellulosematerial, the initially amorphous microspheres crystallized directly inthe presence of the vapors into a stable polymorph. Similar results wereobtained in another experiment by using acetone.

To evaluate stability of the astemizole microspheres, the microsphereswere placed in aqueous solution at 40° C. and observed by opticalmicroscopy after 76 days.

Example 5 Astemizole Pellets

In the case of astemizole pellets, immediately after congealing themolten raw material at −50° C. the pellets showed a high content ofamorphous material. However, the exposure of 150 mg of astemizolepellets in a recipient of approximately 0.5 L for 24 hours at 30° C. tothe vapors of ethyl acetate contained in a porous cellulose material ledto crystallization of the pellets without any modification on theparticle shaper Similar results were obtained by using acetone inanother experiment.

Example 6 Cholesterol Microspheres

Immediately after being produced by the same spray/congealing as for theprevious substances, cholesterol microspheres showed amorphous content.No polymorphs have been reported for cholesterol.

When 100 mg of the microspheres were placed in a recipient ofapproximately 0.5 liters and exposed for 8 hours at 30° C. to the vaporsof 1 mL of acetic acid kept in a porous cellulose material, theinitially amorphous microspheres crystallized completely.

Crystallization of Mixtures of Substances

Mixing different substances in melt congealed shaped particles ofingredients can provide important advantages. Amongst them are:modulating the dissolution rates, lowering the melting point, dilutingthe active ingredients, improving the chemical stability of mainingredients, etc. Thus, the ability to crystallize particles composed ofmixtures of substances increases very importantly the range ofapplications of melt congealed solids in health and other areas.

Many mixtures of substances can be melted and congealed. However,because of the different physical characteristics of each component,such mixtures tend to form complex metastable structures on congealingand, with the exception of eutectic mixtures, it is impossible tocrystallize them because one of the substances can melt before reachingthe transition-point temperature.

As above, particles comprising pluralities of allotropic organiccompounds are likewise suitable for the solid state crystallization ofthe present invention. The crystallization is complete and the resultingparticles are stable in both water and dry environments at the usualtemperatures of storage and use.

Example 7 Microspheres of a Mixture of 40% 17β Estradiol and 60%Cholesterol

The microspheres of this mixture were obtained by melting togetherthe,components and, as for the pure substances, sprayed into dropletsand congealed into microspheres. They initially showed a high amorphouscontent.

When the microspheres were placed in a recipient of approximately 7liters and exposed for 24 hours at 30° C. to the vapors of 8 mL ofethanol kept in a porous cellulose material, the initially amorphousmicrospheres crystallized completely in the presence of the vapors.

The microspheres were dried at 60° C. in a vacuum for 24 hours andresidual ethanol present in the microspheres was less than 0.01%.

To evaluate the stability of the microspheres, non-crystallizedmicrospheres (melt-congealed only) and microspheres according to thepresent invention were separately placed in aqueous solution at 40° C.and observed by optical microscopy after 82 days. As observed by opticalmicroscopy, the microspheres crystallized according to the presentinvention remained stable over time when placed in water, whereas thenon-crystallized microspheres did not.

Stability in Vivo

In the case of slow release injected or implanted medicinal drugs, thephysical integrity of the particles after their administration to thepatient is essential to assure the desired rates of delivery and thereproducibility of effect. Thus, the stability in vivo of themicrospheres described in the previous example was checked in NewZealand male rabbits.

Optical microscopy photographs taken 1, 4, 7 and 14 days afterintramuscular injection showed that the microspheres remain whole, untilthey have finally dissolved. For comparison, microspheres that had notbeen crystallized were also injected. Their optical microscopyphotographs showed that these microspheres changed into non-sphericalshapes.

Example 8 Microspheres of a Mixture of 10% 17β Estradiol & 90%Cholesterol

As for the previous example, the microspheres of this mixture wereobtained by melting together the components, sprayed into droplets andcongealed into microspheres. Initially, they showed a high amorphouscontent.

When the microspheres were placed in a recipient of approximately 7.0liters and exposed for 24 hours at 5° C., to the vapors of 8 mL ofethanol kept in a porous cellulose material, the initially amorphousmicrospheres crystallized completely in the presence of the vapors.

The microspheres were later dried at 60° C. in a vacuum for 24 hours andthe residual ethanol present in the microspheres was less than 0.01%.

To evaluate stability of the crystallized microspheres, they were placedin aqueous solution at 40° C. and observed by optical microscopy after141 days.

Example 9 Microspheres of a Mixture of 95.2% Progesterone & 4.8% 17βEstradiol

As for the previous examples the microspheres of this mixture wereobtained by melting together the components, sprayed into droplets andcongealed into microspheres. Initially, they showed a high amorphouscontent.

When the microspheres were placed in a recipient of approximately 7liters and exposed for 24 hours at 20-25° C. to the vapors of 2 mL ofethanol kept in a porous cellulose material, the initially amorphousmicrospheres crystallized completely in the presence of the vapors.

The microspheres were later dried at 60° C. in a vacuum for 24 hours andthe residual ethanol present in the microspheres was less than 0.01%.

Example 10 Microspheres of a Mixture of 60% Progesterone & 40%Cholesterol

As for the previous examples the microspheres of this mixture wereobtained by melting together the components, sprayed into droplets andcongealed into microspheres. They initially showed a high amorphouscontent.

When the microspheres were placed in a recipient of approximately 7liters and exposed for 24 hours at 30° C. to the vapors of 2 mL ofethanol kept in a porous cellulose material, the initially amorphousmicrospheres crystallized completely in the presence of the vapors.

The microspheres were later dried at 60° C. in a vacuum for 24 hours andthe residual ethanol present in the microspheres was less than 0.01%.

Thus, it is clear that the method of the present invention is widelyapplicable in forming stable, crystallized particles, microspheres andpellets of a variety of organic compounds and mixtures that maintaintheir shape in aqueous solution. Hence, the present method should findsignificant utility in the manufacture of pharmaceuticals andpharmaceutical compositions, particularly where treatment calls foradministration of the pharmaceutical in a slow release formulation.

While some embodiments of the present invention have been shown ordescribed herein, it will be apparent to those skilled in the art thatvarious modifications may be made to the crystallization process withoutdeparting from the spirit and scope of the present invention.

What is claimed is:
 1. A method for forming a plurality of storagestable particles of uniform shape consisting essentially of a pluralityof allotropic organic compounds, each of which is of a uniformcrystalline character, said method comprising: (1) forming a mixtureconsisting essentially of a plurality of allotropic organic compoundsthat are in a mixed crystalline, amorphous, or crystalline and amorphousform; (2) melt congealing said mixture into particles of uniform shape;(3) effecting a solid state crystallization of said particles byexposing said particles to vapors of a solvent of each of saidallotropic organic compounds for sufficient time to permit the solidstate crystallization of said particles; and (4) recovering saidparticles wherein said particles have retained said uniform shape andconsist of a plurality of crystalline domains of uniform crystallinecharacter of each of the allotropic organic compounds.
 2. The method ofclaim 1, wherein the uniform shape is a microsphere of about 10 to about300 microns.
 3. The method of claim 1, wherein one of the allotropicorganic compounds is cholesterol.
 4. The method of claim 1, wherein oneof the allotropic organic compounds is selected from the groupconsisting of 17-β-estradiol, estrogen, testosterone, progesterone, andcholesterol.
 5. The method of claim 1, wherein the particles are ofuniform shape but vary in diameter from about 1 to about 1,000 microns.6. A method for forming a plurality of particles of uniform shapecomprising: (1) forming a mixture of allotropic organic compoundsconsisting essentially of a combination of cholesterol and one or morepharmacotherapeutic agents selected from the group consisting of17-β-estradiol, estrogen, testosterone, progesterone, cholesterol, andmixtures thereof; (2) melt congealing said mixture into sphericalparticles of diameter of about 10 to about 300 microns; (3) effecting asolid state crystallization of said microspheres by exposing saidparticles to vapors of a solvent of each of said allotropic organiccompounds for sufficient time to permit the solid state crystallizationof said particles; and (4) recovering said particles wherein saidrecovered particles have retained the size and shape of the meltcongealed spherical particles formed in step (2), and each allotropicorganic compound within the spherical particle is of uniform crystallinecharacter.
 7. A method for effecting a solid state crystallization of aplurality of particles consisting essentially of a plurality ofallotropic molecular organic compounds, said method comprising: (1)creating a formulation consisting essentially of a plurality ofallotropic molecular organic compounds of mixed crystalline, amorphous,or both crystalline and amorphous forms; (2) melt congealing saidformulation into microspheres of uniform size, wherein said size is adiameter ranging from about one to 1,000 microns; (3) exposing saidmicrospheres to an atmosphere that is below the melting temperature andpressure of each of said allotropic molecular organic compounds andwhich is saturated with a solvent for each of said allotropic molecularorganic compounds for a time sufficient to effect solid statecrystallization of said microspheres; and (4) recovering saidmicrospheres, wherein each of said allotropic organic compounds in saidrecovered microspheres is of a uniform crystalline structure, saidmicrospheres have retained the dimensions of the microspheres fabricatedin step (2), and said microspheres retain said dimensions on storage inaqueous media for at least about one month.
 8. A method for effecting asolid state crystallization of a plurality of particles consistingessentially of a plurality of allotropic molecular organic compounds,said method comprising: (1) creating a formulation consistingessentially of a plurality of allotropic molecular organic compounds ofmixed crystalline, amorphous, or both crystalline and amorphous forms;(2) melt congealing said formulation into microspheres of variousdiameters ranging from about one to about 1,000 microns; (3) exposingsaid microspheres to an atmosphere that is below the melting temperatureand pressure of each of said allotropic molecular organic compounds andwhich is saturated with a solvent for each of said allotropic molecularorganic compounds for a time sufficient to effect solid statecrystallization of said microspheres; and (4) recovering saidmicrospheres, wherein each of said allotropic organic compounds in saidrecovered microspheres is of a uniform crystalline structure, saidmicrospheres have retained the dimensions of the microspheres fabricatedin step (2), and said microspheres retain said dimensions on storage inaqueous media for at least about one month.